Effects of systemic immunosuppressive therapies for moderate‐to‐severe eczema in children and adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of systemic immunosuppressive treatments for people with moderate‐to‐severe atopic eczema.
Background
Atopic eczema, synonymous with atopic dermatitis or just eczema is a chronic, inflammatory skin disease that affects between 5‐20% of children and 2‐5% of adults worldwide (DaVeiga 2012; Johansson 2004). Due to the high global prevalence and disability caused by atopic eczema both in children and adults, this disease can be considered as a significant world‐wide burden both for the affected patients and their families as well as for society. In most individuals, atopic eczema manifests in the first year of life. In about half of children, the disease goes into remission at school age (Williams 2005). However, in a subset of children with atopic eczema, the course of the disease is more chronic and episodic (Schmitt 2009; Schmitt 2011b). In those children with early onset moderate‐to‐severe disease and concomitant atopic diseases such as food and respiratory allergies, atopic eczema frequently persists until and into adulthood (Williams 2005). About one third of children with early onset atopic eczema go through the so‐called 'atopic march' (Spergel 2003), and may develop other allergic diseases. Response to therapy and adverse events may differ between children and adults. Recent studies also suggest a relationship of atopic eczema with psychiatric disorders such as depression and attention‐deficit or hyperactivity disorder (Schmitt 2009; Schmitt 2010a).
Disease symptoms such as pruritus (itch) with resulting excoriations and sleep disturbance, and the intensity and extent of clinical signs of eczema such as erythema, oedema, papulation, dryness, lichenification, and soreness of the skin can have an important impact on a person's quality of life (Charman 2005; Schmitt 2007b; Smaldone 2007). On physical and psychological grounds, atopic eczema may cause stress, and may adversely affect school and work performance, recreational activities and relationships (van Joost 1994; Veien 2005). In addition, individuals are burdened by the impact of the visibility of the affected areas of skin. Frequent scratching also often leads to skin infections (Williams 2005).
The wide variety of outcomes reported in eczema trials constitutes a significant barrier towards evidence‐based decision making in atopic eczema treatment. Based on a more general perspective, 73% of 45 Co‐ordinating Editors of Cochrane Review Groups who were surveyed, thought that a core outcome set for effectiveness trials should be used routinely in the 'Summary of finding' tables (Kirkham 2013). For atopic eczema, a multi‐perspective Delphi study conducted by the initiators of the Harmonising Outcome Measures in Eczema (HOME) Initiative defined clinical signs (measured by means of a physician‐assessed instrument), symptoms of eczema, quality of life and long‐term course of eczema as the core outcome domains to be applied in all future eczema trials (Schmitt 2010b). It has been defined at the 'HOME 4' meeting in 2015, that anything that patients report or complain of is a symptom. Examples are itch, redness, or burning of the skin. Clinical signs are physician or investigator‐assessed visible features of eczema and include the intensity and extent of lesions or lesion characteristics such as lichenification, excoriation, erythema, papulation (Schmitt 2014).
Please see the glossary for explanations of terms we have used in the protocol (Table 1).
| Term | Explanation |
| Aetiology | The cause of the disease |
| Attention‐deficit or hyperactivity disorder (often known as ADHD) | This is a developmental neuropsychiatric disorder that causes problems such as attention deficits, hyperactivity, or impulsiveness which are not appropriate for a person's age |
| Causative treatments | Therapies that modify the cause of a disease rather than its symptoms only. Causative treatments have the potential to modify the course of disease and induce long‐term control or even healing without the need to stay on medication |
| Clinical signs | Physician‐assessed signs of disease, such as dryness or redness |
| Cohorts | A group of people with a particular characteristic in common such as age, date of birth, etc. |
| Concomitant | Other (adjuvant) treatment that is given in addition to the intervention under study |
| Immunologic functions | The process of an immunologic reaction |
| Off‐label | Use of a medication for a condition for which it has not been authorised |
| Relapsing | This term refers to the return of a condition or symptoms |
| Symptoms | Patient‐reported effects of the disease, such as itching or sleep‐deprivation |
Description of the condition
The exact aetiology of atopic eczema remains unclear. There are possible environmental triggers such as water hardness, hygiene practices, and being prescribed antibiotics early in life (Flohr 2014). However, there is a strong association with genetic factors, in particular filaggrin skin barrier gene loss‐of‐function mutations, making a primary skin barrier defect the likely primary trigger of eczematous skin inflammation (Flohr 2014; McAleer 2013). Although our increasing understanding of the aetiology of atopic eczema has led to novel therapeutic approaches in experimental settings (for instance through mechanisms to increase filaggrin synthesis in the epidermis), such treatments, which are targeting the cause of the disease, are not available as yet. For the present, the mainstay therapeutic approach aims to remove trigger factors, such as skin irritants, and to suppress skin inflammation either topically (topical corticosteroids or calcineurin inhibitors or phototherapy) or systemically with immune‐suppressive medication, such as ciclosporin or methotrexate (Bieber 2008; Flohr 2014; Schram 2011).
Atopic dermatitis is characterised by cutaneous inflammation and an immune dysregulation with a T helper 2 cell response. Epidermal barrier dysfunction also plays an important role.
The stratum corneum protects against infection, dehydration, chemicals and mechanical stress and filaggrin is a major structural protein of the stratum corneum (Sandilands 2009). The filaggrin gene encodes for profilaggrin, which is dephosphorylated and processed into multiple copies of filaggrin. During terminal differentiation of the keratinocytes to corneocytes in the granular layer, keratinocytes replace their plasma membrane by a solid layer called the "cornified envelope", which is composed of various proteins, including filaggrin, involucrin and loricrin (Sandilands 2009). Filaggrin also leads to aggregation of the keratin filaments, thereby leading to compaction and flattening of the corneocyte. In the stratum corneum, filaggrin is further broken down by several enzymes including caspase‐14 and bleomycin hydrolase to amino acids and their derivatives which are the main constituents of the collectively known natural moisturising factors. Components of the natural moisturising factors contribute to the hydration of the skin and also play a role in regulating the pH value, which is important for local protease activity and defense against microorganisms such as Staphylococcus aureus, and therefore the natural moisturising factors contribute an important role to the barrier function (Thyssen 2014).
There is a need for research investigating skin barrier properties during, and after systemic immunomodulation in patients with and without filaggrin gene mutations. We need to find out whether there are implications for differences in management (more topical treatments, higher doses, longer duration of systemics) in clinical practice between atopic dermatitis patients with or without filaggrin gene mutations.
Description of the intervention
Moderate‐to‐severe atopic eczema that cannot be sufficiently controlled by the avoidance of individual specific and unspecific provocation factors, daily use of topical emollients and the intermittent use of topical anti‐inflammatory treatments or phototherapy requires systemic immunosuppressive treatment. Patients with moderate‐to‐severe atopic eczema that adequately respond to topical treatments alone do not require systemic anti‐inflammatory treatment (Ring 2012). For the purpose of this review, "immunosuppressive treatment" is used synonymously with "anti‐inflammatory treatment" and "immune‐modulatory treatment", as we consider immunosuppression as the main mode of action of the interventions investigated. We are aware that immunosuppression is usually also related to modulation of the immune response. In the absence of an agreed definition these patients are classified as having moderate‐to‐severe atopic eczema in this review (Schmitt 2011a).
Systemic therapies include several conventional immunosuppressive agents such as glucocorticosteroids, ciclosporin A, methotrexate, azathioprine, interferon‐gamma, intravenous immunoglobulins, and mycophenolate mofetil or mycophenolic acid (Roekevisch 2013; Schmitt 2007a). Additionally, biologic treatments are currently being developed for the treatment of moderate‐to‐severe atopic eczema (Beck 2014).
The interventions of interest in this systematic review are all systemic immunosuppressive agents including, but not necessarily limited to ciclosporin A, methotrexate, azathioprine, interferon‐gamma, mycophenolate mofetil, and biologics.
How the intervention might work
The different systemic immunosuppressive treatments used for moderate‐to‐severe atopic eczema symptomatically suppress skin and systemic inflammation to control disease signs and symptoms (Roekevisch 2013; Schmitt 2007a; Simon 2014; Slater 2015). Some have also been shown to increase quality of life (Roekevisch 2013). The general mode of action of all systemic immunosuppressive treatments for atopic eczema is the interruption of the inflammatory pathways involved in atopic eczema. Treatment strategies developed decades ago, such as systemic glucocorticosteroids, act in a non‐specific manner and suppress several immunologic functions, not all of which are relevant for atopic eczema, whereas more recently developed agents more specifically target atopic eczema‐relevant immunologic functions (Beck 2014; Simon 2014).
The potential targets for therapeutic intervention are as follows.
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Ciclosporin A is a calcineurin inhibitor. The immunosuppressive role of ciclosporin A can be explained by inhibition of the transcription of T‐cell cytokine genes. In addition to inhibition of interleukin‐2, there is also an inhibitory effect on interleuki‐3, interleuki‐4, granulocyte macrophage colony‐stimulating factor), tumour necrosis factor‐alpha, and interferon‐gamma expression (Faulds 1993).
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Methotrexate is a folic acid antagonist and has already in the past proved to be effective in chronic inflammatory diseases such as psoriasis and rheumatoid arthritis. The precise mechanism of action is not clear but the anti‐inflammatory effects may, in part, act via adenosine pathways (Braun 2009; Kalb 2009).
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Azathioprine, a purine analogue, exerts cytotoxic and immunosuppressive effects by inhibiting de novo purine biosynthesis (Dutz 1998).
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Mycophenolate mofetil is a purine biosynthesis inhibitor. The active ingredient of both mycophenolic acid and mycophenolate mofetil interferes with de novo purine biosynthesis, which may inhibit the synthesis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). In addition, the proliferative response of both B and T lymphocytes is inhibited. The enteric‐coated form of mycophenolic acid (as its sodium salt) has entered the market with the aim of reducing gastrointestinal problems: the coating delays the release of the active substance in the stomach, possibly resulting in fewer gastrointestinal side effects. In transplant recipients gastrointestinal complaints during treatment with mycophenolate mofetil, have led to people changing to the use of mycophenolic acidA to reduce these symptoms (Abd Rahman 2013).
Oral corticosteroids have a broad anti‐inflammatory effect and are widely used in the treatment of various atopic disorders, including atopic eczema (Nieder 2001; Schmitt 2009).
Why it is important to do this review
Moderate‐to‐severe atopic eczema constitutes a significant burden of disease in children and adults (Carroll 2005; McAleer 2012). People with moderate‐to‐severe atopic eczema are often difficult to treat (Ring 2012), and guidelines do not provide a clear treatment algorithm and are frequently not based on a systematic critical appraisal of the published evidence (Darsow 2010; Sidbury 2014). Most treatments are used without marketing authorisation for the given condition, making clinical decision making even more complicated. Recently, a survey among 700 dermatologists and paediatricians from eight European countries identified great variation in treatment approaches in children and adolescents with moderate‐to‐severe atopic eczema, in particular with regard to systemic immunosuppressive therapies (Proudfoot 2013).
We have undertaken two systematic reviews on systemic immunosuppressives for moderate‐to‐severe atopic eczema, with the most recent one covering the literature until June 2012 (Roekevisch 2013; Schmitt 2007a). These previous reviews mainly focused on clinical signs as the outcome of interest, and did not extensively appraise the evidence on the core outcome domains (Schmitt 2010b), symptoms, quality of life and long‐term control of flares. They did not have a focus on treatment safety, although safety considerations play an important role in clinical decision‐making, especially if treatments are prescribed off‐label, as is the case in children, nor did they separate adult and paediatric cohorts. They also did not include biological therapies which are starting to be tested in people suffering from atopic eczema. Furthermore, this review is important because of further advances in the treatment of atopic eczema, specifically biological therapies.
Objectives
To assess the effects of systemic immunosuppressive treatments for people with moderate‐to‐severe atopic eczema.
Methods
Criteria for considering studies for this review
Types of studies
We will include all published and unpublished randomised controlled trials (RCTs), both blinded and unblinded as well as open label extensions of RCTs, irrespective of publication language that reports efficacy or safety of one or more systemic immunosuppressive treatments for children or adults with atopic eczema.
We will include placebo‐controlled, head‐to‐head trials and multi‐arm studies.
Types of participants
We will consider people of all ages with at least moderate‐to‐severe atopic eczema and irrespective of gender.
Due to the absence of an established definition of moderate‐to‐severe atopic eczema, we will adopt the definition of disease severity as stated by the authors of the respective studies. Hence, we will consider RCTs that included subjects defined by the study authors as people with 'moderate‐to‐severe atopic eczema', or 'non‐adequately controlled atopic eczema despite the use of topical anti‐inflammatory therapy', or 'refractory atopic eczema', or with 'moderate‐to severe atopic eczema according to published severity criteria' (Schmitt 2013). We will summarise the range of definitions that are included in the studies chosen for inclusion.
We will exclude trials with "mild" cases, even if only one is reported.
Types of interventions
To be considered eligible, studies need to investigate the efficacy or safety or tolerability of at least one systemic immunosuppressive or immunomodulating therapy for atopic eczema, or a combination of treatments from the following.
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Immunosuppressive therapies, e.g. ciclosporin A, azathioprine, methotrexate, mycophenolate mofetil, pimecrolimus as well as oral glucocorticosteroids like prednisolone, psoralen‐ultraviolet A.
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Other primary immunomodulating medications, e.g. tacrolimus, interferon‐gamma, intravenous immunoglobulin, and biologics.
We will not include studies which exclusively investigate antihistamines, antibiotics, leukotriene antagonists, vaccinations (for example Mycobacterium vaccae suspension), phototherapy other than psoralen‐ultraviolet A, or topical treatments.
Types of outcome measures
In accordance with the global, multidisciplinary HOME Initiative, the core outcome domains for eczema trials are as follows (Schmitt 2012).
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Clinical signs.
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Symptoms.
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Health‐related quality of life.
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The course of atopic eczema, i.e. flares and severity over time.
Due to the increasing relevance of stratified medicine, we will assess the effect of interventions on biomarkers as a secondary outcome in those studies that also report on at least one of the consented core outcome domains for eczema trials, i.e. clinical signs, symptoms, quality of life, long‐term control of flares (Schmitt 2012). However, we will exclude studies that only report on biomarkers and not on a single core outcome domain.
Primary outcomes
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Mean change in physician‐assessed clinical signs score (e.g. the Severity Scoring of Atopic Dermatitis Index or the Eczema Area and Severity Index)
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Incidence rate of adverse events (all adverse events)
Secondary outcomes
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Mean change in eczema symptoms score (e.g. Patient‐oriented Eczema Measure; Visual Analog Scale score for pruritus)
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Mean change in quality of life (e.g. the Dermatology Life Quality Index)
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Mean number of atopic eczema flares
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Withdrawal rates (total, due to adverse event, due to treatment failure)
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Incidence rate of adverse events and serious adverse events (as defined in the trial)
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Mean change in biomarkers
Timing of outcomes
We define short term (≤ 16 weeks of treatment) and long term or maintenance (> 16 weeks of treatment)
Search methods for identification of studies
We aim to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress).
Electronic searches
We will search the following databases for relevant trials:
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the Cochrane Skin Group Specialised Skin Register;
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Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Library;
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MEDLINE via Ovid (from 1946);
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EMBASE via Ovid (from 1974);
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Latin American and Caribbean Health Science Information database (LILACS) (from 1982); and
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the Global Resource of EczemA Trials (GREAT) database, Centre of Evidence Based Dermatology, University of Nottingham (www.greatdatabase.org.uk/GD4/Search/index.php).
We have devised a draft search strategy for RCTs for MEDLINE (Ovid) (Appendix 1). We will use this strategy as the basis for other databases listed above.
Trials registers
We will search the following trials registers (Appendix 2):
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metaRegister of Controlled Trials (www.controlled‐trials.com);
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ClinicalTrials.gov (www.clinicaltrials.gov);
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Australian New Zealand Clinical Trials Registry (www.anzctr.org.au);
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal (apps.who.int/trialsearch); and
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European Union (EU) Clinical Trials Register (www.clinicaltrialsregister.eu).
Searching other resources
Reference checking
We will check all reference lists of all publications that are retrieved as full papers and potentially relevant, as well as relevant systematic reviews and literature reviews, to identify other potentially relevant reports of trials.
Unpublished literature
We will contact the lead authors of all relevant reports identified, and experts in the field, for additional published and unpublished studies that may be relevant to the review.
Adverse effects
We will not perform a separate search for adverse effects of the target interventions. However, we will examine data on adverse effects from the included studies we identify.
Data collection and analysis
Selection of studies
At least two authors (DK, PS and JS) will independently screen the titles and abstracts of all references identified by electronic database searches. We will code the studies as "eligible" or "ineligible". We will include studies with at least one "eligible" rating for further screening. We will exclude studies that do not fulfil the inclusion criteria (rated as "ineligible") from further consideration. We will maintain a record of all rejected papers and document the reasons for exclusion.
At least two review authors (DK, PS and JS) will independently screen the full‐texts of the remaining potentially relevant studies by applying the pre‐defined inclusion and exclusion criteria. In addition, we will also independently review all other articles identified by the various search strategies that seem relevant (e.g. reference checking, search for unpublished trials). We will provide reasons for the exclusion of papers. We will resolve any disagreement about the relevance of potentially eligible studies through discussion.
We will include placebo‐controlled, head‐to‐head trials and multi‐arm studies. A head‐to‐head trial compares two groups of individuals with the disease of interest, with each group being subject to another treatment option. The aim of such a trial design is the direct comparison of the individual treatment options.
We intend to follow the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement and will create a flow chart for the selection of studies.
Data extraction and management
Two authors (DK, JS) will independently extract data from each included trial using a pilot‐tested data extraction form.
We will extract the following study characteristics for all included studies.
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General: publication status, title, authors, source, country, language of publication, year of publication, duplicate publication.
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Study design: RCT or open label extensions of RCT, date of study, study location, study setting (single or multi‐centre; information on training methods and alignment of assessment methods).
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Participant characteristics: number of persons with atopic eczema included (sample size, total and by intervention), age (mean (±standard deviation (SD)) years); n (%) children (age as defined in study, without age definition < 18 years); adults (age as defined in study, without age definition 18‐64 years); elderly adults (≥ 65 years), sex, severity of atopic eczema, previous treatments, atopic comorbidities, immunoglobulin E levels, eosinophils, filaggrin gene mutations, inclusion and exclusion criteria.
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Intervention: description of intervention, comparison, mode of application, dose, frequency, duration of active treatment, follow up, adjuvant treatments.
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Baseline characteristics of intervention and comparison: interventions (type of interventions, number of randomised participants, number of excluded participants after randomisation, mean age, proportion of females), baseline characteristics control (type of treatment, number of participants, mean age, proportion).
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Summary of efficacy: change in clinical signs, change in quality of life, change in symptoms, number of flares, biomarkers.
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Summary of safety or tolerability of systemic therapies: overall withdrawals due to adverse events or for any reasons, total serious adverse events, related serious adverse events, total serious adverse events, total adverse events.
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Matrix of outcome methodology: including core outcome domains of atopic eczema (i.e. clinical signs, symptoms, health‐related quality of life, long‐term control of flares), specific measures (e.g. the Eczema Area and Severity Index, the Severity Scoring of Atopic Dermatitis), specific metric used to describe each participant’s results (i.e. change from baseline, time to event), and method of aggregation within each group (e.g. continuous or categorical data).
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Conflict of interest: source of funding, declaration of interest (authors' and sponsors' conflict of interest as a potential source for bias (Brennan 2006; Sharek 2012). When no information on funding or conflict of interest is provided, we will assume that there was none.
We will define the mean change in efficacy outcome as the mean change in the primary outcome measure clinical signs (with specific instruments such as theSeverity Scoring of Atopic Dermatitis Index, and the Eczema area and severity Index) from baseline to the end of active treatment. We will also analyse relapse rates (recurrence of signs and symptoms), duration of remission, and the course of atopic eczema with follow‐up. If not mentioned in the paper, we will calculate the mean change in clinical severity using absolute scores at baseline and the end of active treatment, extracted from either the text, a presented figure or graph.
We will analyse short‐term (≤ 16 weeks) as well as long‐term or maintenance (> 16 weeks) treatment separately, as well as treatment efficacy in children (< 18 years) versus adults (≥ 18 years) if adequate data is available. To compare safety data of the different treatments, we will calculate the incidence rates (%) per participant per week for adverse events, serious adverse events and withdrawals due to adverse events using the formula: [number of events divided by (number of patients multiplied by duration of RCT in weeks)] multiplied by 100.
We will resolve disagreements about data extraction by discussion.
Assessment of risk of bias in included studies
Two independent authors (DK, JS) will assess the risk of bias in each of the included studies using the Cochrane's tool for assessing risk of bias (Higgins 2011a; Higgins 2011b). We will judge the risk of bias in each study against each criterion as 'low', 'high' or 'unclear' risk of bias (either lack of information or uncertainty over the potential of bias). The relative importance of the different domains will be considered to be equal. For a summary assessments of the risk of bias within the studies we intend to follow the approach as suggested by the Cochrane Handbook for Systematic Reviews of Interventions: If one domain is “high risk”, we will classify the overall study as at high risk of bias. If all domains are low risk we will classify the study as low risk. If one domain is "unclear" for at least one domain, we will classify the overall study as at unclear risk of bias. If all domains are "low risk", we will classify the overall study as at low risk of bias (Higgins 2011a).
The main criteria applied to measure the risk of bias will include:
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random sequence generation;
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allocation concealment;
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blinding of participants and personnel;
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blinding of outcome assessment;
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incomplete outcome data;
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selective outcome reporting;
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other bias.
If a RCT had drop‐outs and an intention‐to‐treat (ITT) analysis was used but no information on the handling of the missing data was given, we will judge the risk of bias as “unclear” due to incomplete outcomes. If drop‐out rate is < 20%, we will consider it as low risk of bias.
In case of differences in opinion, we will consult a third author (JS). We will illustrate our results using a 'risk of bias' table for each individual study as well as a 'risk of bias' summary.
Measures of treatment effect
For continuous outcomes like clinical signs, symptoms, quality of life, flares and changes in biomarkers, we will calculate mean differences (MDs) and mean changes in group differences with corresponding 95% confidence intervals (CIs).
For dichotomous outcome data (i.e. rates of adverse events and withdrawals), we will use risk ratios (RRs) with 95% CIs. We will calculate the number needed to treat to benefit (NNTB) with corresponding 95% CIs.
Unit of analysis issues
For cross‐over studies, we will only use the period prior to cross‐over in order to avoid information bias due to carry‐over effects. For studies with multiple intervention groups, we will include two or more correlated comparisons and will account for the correlation if needed.
We will exclude cluster‐RCTs.
Dealing with missing data
We will contact study authors for any missing data from RCTs published in the past 10 years.
In case of missing data about key study characteristics or outcomes, we will contact the original investigators for additional information. If we do not receive an answer from the authors within three weeks, we will perform the analyses based on available information and record that the missing data was not retrieved from the corresponding author.
Specifically, we will request the following data from the study author should we find that such information was missing from the study publication.
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Study design: RCT or open label extensions of RCT, date of study, study location, study setting.
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Participant characteristics: number of persons with atopic eczema included (sample size, total and by intervention), age, n (%) of children, adults and elderly, gender, severity of atopic eczema, previous treatments, atopic comorbidities.
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Description of intervention.
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Primary and secondary outcomes.
Assessment of heterogeneity
We will apply qualitative and statistical methods to assess clinical diversity and statistical heterogeneity of the included studies, respectively. In case of obvious clinical diversity, we will not perform meta‐analysis. We will investigate the existence of statistical heterogeneity using the computation of the I² statistic, which monitors the extent to which studies cannot be compared with each other ("inconsistency"). We will also pursue subgroup analyses and, if possible, meta‐regression. We will consider baseline severity of atopic eczema, instruments to assess efficacy and the proportion of children and adults as potential sources of heterogeneity.
Assessment of reporting biases
To investigate publication bias, we will construct funnel plots where there are a minimum of 10 studies for any outcome (Sterne 2011). We will assess the funnel plots visually and investigate any asymmetry found.
We will re‐examine our search for grey literature when we suspect missing studies with negative results and reconsider the generic search terms, if we suspect missing studies with positive results.
Data synthesis
To critically appraise clinical diversity, two authors (DK, JS) will perform a narrative synthesis of all the included studies and seek agreement from other co‐authors. We will analyse clinically homogeneous studies using a random‐effects meta‐analysis model; in cases where pooling is not advisable due to heterogeneity, we will only report a narrative synthesis.
For statistical heterogeneity, we will only pool studies where there are five eligible comparisons for each outcome. When determining the heterogeneity of pooled studies, if I² is found to be < 25% (Higgins 2011a), which indicates low heterogeneity, we will still apply a random‐effects model since we have previously reported that the criteria for a fixed‐effect meta‐analysis are not met (i.e. heterogeneity of outcomes methodology) (Roekevisch 2013). We will present results of meta‐analyses as forest plots.
In cases where pooling is not advisable due to statistical heterogeneity (i.e. I² > 75%), we intend to perform a narrative (qualitative) synthesis only.
We will not pool open‐label extension studies.
If not mentioned in the study publications, we will calculate the mean change in clinical signs, symptoms, and quality of life using absolute scores at baseline and at the end of active treatment, and present relevant findings in a figure or graph.
To compare safety data, we will calculate the incidence rates (%) per participant per week for adverse events, serious adverse events and withdrawals due to atopic eczema using this formula: [number of events divided by (number of patients multiplied by duration of RCT in weeks)] multiplied by 100.
Subgroup analysis and investigation of heterogeneity
We plan to perform the following subgroup analyses if adequate data is available:
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short‐term treatment (≤ 16 weeks);
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long‐term or maintenance treatment (> 16 weeks);
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treatment efficacy in children (< 18 years) versus adults (≥ 18 years);
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impact of filaggrin gene mutation carriage on treatment response.
Sensitivity analysis
We will explore sources of uncertainty with sensitivity and subgroup analyses using meta‐regression models. Sensitivity analyses include the exploration of the influence of the study quality, trial participant characteristics (age, sex), imbalanced drop out and the largest and smallest trials in the analysis on the overall results.
'Summary of findings' table
We plan to include at least one 'Summary of findings' table in our review. We will summarise the primary outcomes for the most important comparison. If we feel there are several major comparisons or that our findings need to be summarised for different populations we will include further 'Summary of findings' tables. We will assess the quality of the body of evidence using the five Grading of Recommendations Assessment, Development and Evaluation (GRADE) considerations namely study limitations, consistency of effect, imprecision, indirectness and publication bias (Higgins 2011a).
| Term | Explanation |
| Aetiology | The cause of the disease |
| Attention‐deficit or hyperactivity disorder (often known as ADHD) | This is a developmental neuropsychiatric disorder that causes problems such as attention deficits, hyperactivity, or impulsiveness which are not appropriate for a person's age |
| Causative treatments | Therapies that modify the cause of a disease rather than its symptoms only. Causative treatments have the potential to modify the course of disease and induce long‐term control or even healing without the need to stay on medication |
| Clinical signs | Physician‐assessed signs of disease, such as dryness or redness |
| Cohorts | A group of people with a particular characteristic in common such as age, date of birth, etc. |
| Concomitant | Other (adjuvant) treatment that is given in addition to the intervention under study |
| Immunologic functions | The process of an immunologic reaction |
| Off‐label | Use of a medication for a condition for which it has not been authorised |
| Relapsing | This term refers to the return of a condition or symptoms |
| Symptoms | Patient‐reported effects of the disease, such as itching or sleep‐deprivation |
